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Genetic Testing for BRCA1/2

TON - August 2013 Vol 6 No 7 published on September 4, 2013 in Genetic Counseling
Angela Long
Cristi Radford, MS, CGC

The announcement this spring by Angelina Jolie that she had undergone a risk-reducing double mastectomy after learning she carried a mutation in the BRCA1 gene, as well as the recent US Supreme Court decision on gene patenting, has resulted in an influx of questions to both genetic providers and support organizations about hereditary breast cancer. Below are some of the questions encountered by Angela Long, president of Breast Investigators.

Is BRCA1/2 the only hereditary breast cancer syndrome?

No. BRCA1/2 are genes that help prevent breast, ovarian, and several other cancers. When the genes have mutations, individuals are at increased risk of developing the associated cancers. Often, individuals with a mutation in BRCA1 and/or BRCA2 are referred to as having hereditary breast and ovarian cancer syndrome, also known as HBOC. Although BRCA1/2 mutations are currently believed to account for the majority of known hereditary breast and ovarian cancer cases, it is estimated that between 10% and 25% of individuals with breast cancer have an underlying gene mutation that has placed him or her at an increased risk of developing breast cancer. The risk conveyed by the gene mutation may increase breast cancer risk anywhere from 2- to 20+-fold.1 Additionally, individuals may be at risk for a variety of other cancers, including skin, colorectal, uterine, ovarian, prostate, thyroid, etc. For this reason, it is imperative that an individual deemed at risk for a hereditary breast cancer syndrome be assessed for all possible syndromes via targeted genetic testing. Genetic diagnosis allows an individual’s healthcare team to develop a personalized surveillance and treatment plan targeting the cancers he or she is at high risk of developing. Additionally, it allows family members to be tested for the familial mutation in the family.

Is Myriad Genetics the only laboratory that performs BRCA1/2 testing?

BRCA testing became commercially available in 1996, and Myriad Genetics was granted patents on BRCA1/2 in the late 1990s. As a result, Myriad quickly became the sole provider of BRCA1/2 testing in the United States.2-4 However, on June 13, 2013, the US Supreme Court ruled that naturally occurring DNA is not patent eligible merely because it has been isolated, as it is a product of nature.5 As a result, Ambry Genetics and the University of Washington began offering BRCA1/2 testing that week, with many other laboratories announcing plans to offer testing for BRCA1/2 shortly.

If you were tested several years ago or longer and were found to be negative for BRCA1 and BRCA2, are there new tests available to determine if you truly have an inherited gene mutation? What is BART?

Yes. The field of inherited cancer genetics is constantly evolving. Individuals considered at risk to carry an inherited gene mutation should contact their genetic provider on an annual basis to determine if new tests are available. Depending on when an individual underwent testing for BRCA1/2 mutations, he or she may need additional testing for BRCA1/2.

Germline mutations in BRCA1/2 are typically single-base changes or small deletions/insertions; however, depending on the group analyzed, up to 10% of mutations may be large deletions or duplications.6 Most of these large rearrangements cannot be detected by traditional polymerase chain reaction (PCR)–based sequencing reactions. Therefore, depending on the methods of gene analysis used, a separate test may be needed to find large rearrangements that negatively affect gene function.

Myriad Genetics enhanced their BRCA1/2 test in August 2002 to include 5 large rearrangements, followed in August 2006 by the addition of the BRACAnalysis Large Rearrangement Test, also known as BART, on select high-risk samples and for patients who elected to have the test.6 In 2012, the test began to shift to Integrated BRACAnalysis, reflecting the inclusion of BART as part of BRCA1/2 gene analysis.7 Therefore, depending on when an individual underwent testing for BRCA1/2 mutations, he or she may not have had the most comprehensive test, and additional testing for BRCA1/2 mutations may be warranted.

National guidelines reference consideration of other inherited cancer syndromes, such as those caused by mutations in the TP53 and PTEN genes, when BRCA1/2 test results are negative.8 Similar to BRCA1/2, these genes place an individual at increased risk of developing breast cancer; however, they also place an individual at high risk for other cancers, such as sarcomas, brain tumors, uterine cancer, thyroid cancer, and colorectal cancer. Additionally, “inherited cancer panels,” which became commercially available in the spring of 2012, examine multiple genes associated with an inherited risk of developing a cancer. The genes included on any given panel vary depending on the laboratory performing the test and the cancer sites of interest and may include both moderately and highly penetrant genes. For example, a recent abstract presented at the 2013 American Society of Clinical Oncology Annual Meeting evaluated 249 African American breast cancer survivors referred for genetic counseling for mutations in 18 known breast cancer genes using a “cancer panel.”9 Almost 1 in 4 study participants (22%) were found to carry a germline mutation, including mutations in BRCA1, BRCA2, CHEK2, PALB2, ATM, and PTEN. Therefore, individuals with negative BRCA1/2 test results who were not assessed for genes other than BRCA1/2 should contact their provider to determine if further genetic testing for other genes is warranted.

If you are a breast cancer survivor of several years, would it be beneficial to have genetic counseling/testing?

Genetic testing has medical management implications for survivors and/or family members at every stage of the cancer continuum. For newly diagnosed women with breast cancer, a genetic diagnosis may affect surgical decisions and/or the use of radiotherapy. For survivors of several years, a woman may opt to have a risk-reducing mastectomy or undergo increased breast surveillance. Additionally, testing may uncover other types of cancers she is at increased risk of developing. Knowing this information allows her healthcare team to work with her to develop a personalized management plan that prevents future cancers or diagnoses them at the earliest, most treatable stage. Genetic testing in the palliative care setting is also beneficial. If a causative gene mutation is identified, this information allows family members to be tested and, if results are positive, for them to take preventive steps. If test results are negative, the family members may not need increased screening for cancer. Sometimes an individual in palliative care is the only cancer survivor available for genetic testing. As genetic testing is most informative when it is performed on the individual most likely to have an inherited gene mutation, the option of testing a survivor is no longer an option after he or she passes.

1. Hollestelle A, Wasielewski M, Martens JW, et al. Discovering moderate-risk breast cancer susceptibility genes. Curr Opin Genet Dev. 2010;20(3):268-276.
2. Williams-Jones B. History of a gene patent: tracing the development and application of commercial BRCA testing. Health Law J. 2002;10:123-146.
3. American Civil Liberties Union (ACLU). Legal challenge to human gene patents: BRCA genes and patents—frequently asked questions. Published May 27, 2009. Accessed July 23, 2013.
4. Kesselheim AS, Mello MM. Gene patenting—is the pendulum swinging back? N Engl J Med. 2010; 362(20):1855-1858.
5. Association for Molecular Pathology et al v Myriad Genetics, Inc., et al, 569 US 1 2 (2013). Accessed July 23, 2013.
6. Judkins T, Rosenthal E, Arnell C, et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012;118(21):5210-5216.
7. Myriad Genetic Laboratories, Inc. Integrated BRACAnalysis® to include BART™. http:// ed+BRACAnalysis+to+Include+BART.pdf. Accessed July 23, 2013.
8. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2013. f_guidelines.asp. Accessed July 23, 2013.
9. Churpek JE, Walsh T, Zheng Y, et al. Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next-generation sequencing. J Clin Oncol. 2013;31(suppl):Abstract CRA1501.

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Last modified: September 9, 2019